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1.  Progression from gestational diabetes to type 2 diabetes in one region of Scotland: an observational follow-up study 
The aim of this study was to investigate long-term risk of type 2 diabetes (T2D) following a diagnosis of gestational diabetes and to identify factors that were associated with increased risk of T2D.
An observational cohort design was used, following up all women diagnosed with gestational diabetes mellitus (GDM) attending a Diabetes Antenatal Clinic in the Dundee and Angus region of Scotland between 1994 and 2004 for a subsequent diagnosis of T2D, as recorded on SCI-DC (a comprehensive diabetes clinical information system).
There were 164 women in the study who were followed up until 2012. One quarter developed T2D after a pregnancy with GDM in a mean time period of around eight years. Factors associated with a higher risk of developing T2D after GDM were increased weight during pregnancy, use of insulin during pregnancy, higher glycated haemoglobin (HbA1c) levels at diagnosis of GDM, and fasting blood glucose.
These findings suggest there is a viable time window to prevent progression from GDM to T2D and highlights those women who are at the greatest risk and should therefore be prioritised for preventative intervention.
PMCID: PMC4320450  PMID: 25643857
Gestational diabetes; Type 2 diabetes; Follow-up; United Kingdom
2.  Glycemic Exposure and Blood Pressure Influencing Progression and Remission of Diabetic Retinopathy 
Diabetes Care  2013;36(12):3979-3984.
This study sought to investigate the progression and regression of diabetic retinopathy (DR) and the effects of population risk factors on the rates of transition across retinopathy stages.
The study cohort consisted of 44,871 observed DR events between the calendar years 1990 and 2011 for 4,758 diabetic patients who were diagnosed at 35 years of age or older. The first retinal observation was recorded within a year from diagnosis, and the result was recorded as free of retinopathy. A multistate Markov model was applied for analyzing the development of DR and its relation to the patterns of changes in risk factors.
We observed a consistent risk effect of HbA1c on the progression (no retinopathy to mild background DR [BDR] hazard ratio per SD of HbA1c [HR] 1.42 [95% CI 1.32–1.52], mild BDR to observable BDR HR 1.32 [95% CI 1.08–1.60], and observable BDR to severe nonproliferative/proliferative DR HR 2.23 [95% CI 1.16–4.29]). Similarly, systolic blood pressure (SBP) and diastolic blood pressure increased the risk for the transition from the asymptomatic phase to mild BDR (HR 1.20 [95% CI 1.11–1.30]) and the mild BDR to observable BDR (HR 1.87 [95% CI 1.46–2.40]), respectively. Regression from mild BDR to no DR was associated with lower SBP (HR 0.79 [95% CI 0.64–0.97]) and lower HbA1c (HR 0.76 [95% CI 0.64–0.89]).
Progression and regression of DR were strongly associated with blood pressure and glycemic exposure.
PMCID: PMC3836116  PMID: 24170761
3.  Association Between BMI Measured Within a Year After Diagnosis of Type 2 Diabetes and Mortality 
Diabetes Care  2013;36(4):887-893.
To describe the association of BMI with mortality in patients diagnosed with type 2 diabetes.
Using records of 106,640 patients in Scotland, we investigated the association between BMI recorded around the diagnosis of type 2 diabetes mellitus (T2DM) and mortality using Cox proportional hazards regression adjusted for age and smoking status, with BMI 25 to <30 kg/m2 as a referent group. Deaths within 2 years of BMI determination were excluded. Mean follow-up to death or the end of 2007 was 4.7 years.
A total of 9,631 deaths occurred between 2001 and 2007. Compared with the reference group, mortality risk was higher in patients with BMI 20 to <25 kg/m2 (hazard ratio 1.22 [95% CI 1.13–1.32] in men, 1.32 [1.22–1.44] in women) and patients with BMI ≥35 kg/m2 (for example, 1.70 [1.24–2.34] in men and 1.81 [1.46–2.24] in women for BMI 45 to <50 kg/m2). Vascular mortality was higher for each 5-kg/m2 increase in BMI >30 kg/m2 by 24% (15–35%) in men and 23% (14–32%) in women, but was lower below this threshold. The results were similar after further adjustment for HbA1c, year of diagnosis, lipids, blood pressure, and socioeconomic status.
Patients categorized as normal weight or obese with T2DM within a year of diagnosis of T2DM exhibit variably higher mortality outcomes compared with the overweight group, confirming a U-shaped association of BMI with mortality. Whether weight loss interventions reduce mortality in all T2DM patients requires study.
PMCID: PMC3609520  PMID: 23139375
4.  Reduced Incidence of Lower-Extremity Amputations in People With Diabetes in Scotland 
Diabetes Care  2012;35(12):2588-2590.
To establish the incidence of nontraumatic lower-extremity amputation (LEA) in people with diabetes in Scotland.
This cohort study linked national morbidity records and diabetes datasets to establish the number of people with diabetes who underwent nontraumatic major and minor LEA in Scotland from 2004 to 2008.
Two thousand three hundred eighty-two individuals with diabetes underwent a nontraumatic LEA between 2004 and 2008; 57.1% (n = 1,359) underwent major LEAs. The incidence of any LEA among persons with diabetes fell over the 5-year study period by 29.8% (3.04 per 1,000 in 2004 to 2.13 per 1,000 in 2008, P < 0.001). Major LEA rates decreased by 40.7% from 1.87 per 1,000 in 2004 to 1.11 per 1,000 in 2008 (P < 0.001).
There has been a significant reduction in the incidence of LEA in persons with diabetes in Scotland between 2004 and 2008, principally explained by a reduction in major amputation.
PMCID: PMC3507601  PMID: 23011727
5.  Protocol for a systematic review and individual patient data meta-analysis of prognostic factors of foot ulceration in people with diabetes: the international research collaboration for the prediction of diabetic foot ulcerations (PODUS) 
Diabetes–related lower limb amputations are associated with considerable morbidity and mortality and are usually preceded by foot ulceration. The available systematic reviews of aggregate data are compromised because the primary studies report both adjusted and unadjusted estimates. As adjusted meta-analyses of aggregate data can be challenging, the best way to standardise the analytical approach is to conduct a meta-analysis based on individual patient data (IPD).
There are however many challenges and fundamental methodological omissions are common; protocols are rare and the assessment of the risk of bias arising from the conduct of individual studies is frequently not performed, largely because of the absence of widely agreed criteria for assessing the risk of bias in this type of review. In this protocol we propose key methodological approaches to underpin our IPD systematic review of prognostic factors of foot ulceration in diabetes.
Review questions;
1. What are the most highly prognostic factors for foot ulceration (i.e. symptoms, signs, diagnostic tests) in people with diabetes?
2. Can the data from each study be adjusted for a consistent set of adjustment factors?
3. Does the model accuracy change when patient populations are stratified according to demographic and/or clinical characteristics?
MEDLINE and EMBASE databases from their inception until early 2012 were searched and the corresponding authors of all eligible primary studies invited to contribute their raw data. We developed relevant quality assurance items likely to identify occasions when study validity may have been compromised from several sources. A confidentiality agreement, arrangements for communication and reporting as well as ethical and governance considerations are explained.
We have agreement from the corresponding authors of all studies which meet the eligibility criteria and they collectively possess data from more than 17000 patients. We propose, as a provisional analysis plan, to use a multi-level mixed model, using “study” as one of the levels. Such a model can also allow for the within-patient clustering that occurs if a patient contributes data from both feet, although to aid interpretation, we prefer to use patients rather than feet as the unit of analysis. We intend to only attempt this analysis if the results of the investigation of heterogeneity do not rule it out and the model diagnostics are acceptable.
This review is central to the development of a global evidence-based strategy for the risk assessment of the foot in patients with diabetes, ensuring future recommendations are valid and can reliably inform international clinical guidelines.
PMCID: PMC3599337  PMID: 23414550
6.  Risk of Cardiovascular Disease and Total Mortality in Adults with Type 1 Diabetes: Scottish Registry Linkage Study 
PLoS Medicine  2012;9(10):e1001321.
Helen Colhoun and colleagues report findings from a Scottish registry linkage study regarding contemporary risks for cardiovascular events and all-cause mortality among individuals diagnosed with type 1 diabetes.
Randomized controlled trials have shown the importance of tight glucose control in type 1 diabetes (T1DM), but few recent studies have evaluated the risk of cardiovascular disease (CVD) and all-cause mortality among adults with T1DM. We evaluated these risks in adults with T1DM compared with the non-diabetic population in a nationwide study from Scotland and examined control of CVD risk factors in those with T1DM.
Methods and Findings
The Scottish Care Information-Diabetes Collaboration database was used to identify all people registered with T1DM and aged ≥20 years in 2005–2007 and to provide risk factor data. Major CVD events and deaths were obtained from the national hospital admissions database and death register. The age-adjusted incidence rate ratio (IRR) for CVD and mortality in T1DM (n = 21,789) versus the non-diabetic population (3.96 million) was estimated using Poisson regression. The age-adjusted IRR for first CVD event associated with T1DM versus the non-diabetic population was higher in women (3.0: 95% CI 2.4–3.8, p<0.001) than men (2.3: 2.0–2.7, p<0.001) while the IRR for all-cause mortality associated with T1DM was comparable at 2.6 (2.2–3.0, p<0.001) in men and 2.7 (2.2–3.4, p<0.001) in women. Between 2005–2007, among individuals with T1DM, 34 of 123 deaths among 10,173 who were <40 years and 37 of 907 deaths among 12,739 who were ≥40 years had an underlying cause of death of coma or diabetic ketoacidosis. Among individuals 60–69 years, approximately three extra deaths per 100 per year occurred among men with T1DM (28.51/1,000 person years at risk), and two per 100 per year for women (17.99/1,000 person years at risk). 28% of those with T1DM were current smokers, 13% achieved target HbA1c of <7% and 37% had very poor (≥9%) glycaemic control. Among those aged ≥40, 37% had blood pressures above even conservative targets (≥140/90 mmHg) and 39% of those ≥40 years were not on a statin. Although many of these risk factors were comparable to those previously reported in other developed countries, CVD and mortality rates may not be generalizable to other countries. Limitations included lack of information on the specific insulin therapy used.
Although the relative risks for CVD and total mortality associated with T1DM in this population have declined relative to earlier studies, T1DM continues to be associated with higher CVD and death rates than the non-diabetic population. Risk factor management should be improved to further reduce risk but better treatment approaches for achieving good glycaemic control are badly needed.
Please see later in the article for the Editors' Summary
Editors' Summary
Background. People with diabetes are more likely to have cardiovascular disease such as heart attacks and strokes. They also have a higher risk of dying prematurely from any cause. Controlling blood sugar (glucose), blood pressure, and cholesterol can help reduce these risks. Some people with type 1 diabetes can achieve tight blood glucose control through a strict regimen that includes a carefully calculated diet, frequent physical activity, regular blood glucose testing several times a day, and multiple daily doses of insulin. Other drugs can reduce blood pressure and cholesterol levels. Keeping one's weight in the normal range and not smoking are important ways in which all people, including those with type 1 diabetes can reduce their risks of heart disease and premature death.
Why Was This Study Done? Researchers and doctors have known for almost two decades what patients with type 1 diabetes can do to minimize the complications from the disease and thereby reduce their risks for cardiovascular disease and early death. So for some time now, patients should have been treated and counseled accordingly. This study was done to evaluate the current risks for have cardiovascular disease and premature death amongst people living with type 1 diabetes in a high-income country (Scotland).
What Did the Researchers Do and Find? From a national register of all people with type 1 diabetes in Scotland, the researchers selected those who were older than 20 years and alive at any time from January 2005 to May 2008. This included about 19,000 people who had been diagnosed with type 1 diabetes before 2005. Another 2,600 were diagnosed between 2005 and 2008. They also obtained data on heart attacks and strokes in these patients from hospital records and on deaths from the natural death register. To obtain a good picture of the current relative risks, they compared the patients with type 1 diabetes with the non-diabetic general Scottish population with regard to the risk of heart attacks/strokes and death from all causes. They also collected information on how well the people with diabetes controlled their blood glucose, on their weight, and whether they smoked.
They found that the current risks compared with the general Scottish population are quite a bit lower than those of people with type 1 diabetes in earlier decades. However, people with type 1 diabetes in Scotland still have much higher (more than twice) the risk of heart attacks, strokes, or premature death than the general population. Moreover, the researchers found a high number of deaths in younger people with diabetes from coma—caused by either too much blood sugar (hyperglycemia) or too little (hypoglycemia). Severe hyperglycemia and hypoglycemia happen when blood glucose control is poor. When the scientists looked at test results for HbA1c levels (a test that is done once or twice a year to see how well patients controlled their blood sugar over the previous 3 months) for all patients, they found that the majority of them did not come close to controlling their blood glucose within the recommended range.
When the researchers compared body mass index (a measure of weight that takes height into account) and smoking between the people with type 1 diabetes and the general population, they found similar proportions of smokers and overweight or obese people.
What Do these Findings Mean? The results represent a snapshot of the recent situation regarding complications from type 1 diabetes in the Scottish population. The results suggest that within this population, strategies over the past two decades to reduce complications from type 1 diabetes that cause cardiovascular disease and death are working, in principle. However, there is much need for further improvement. This includes the urgent need to understand why so few people with type 1 diabetes achieve good control of their blood sugar, and what can be done to improve this situation. It is also important to put more effort into keeping people with diabetes from taking up smoking or getting them to quit, as well as preventing them from getting overweight or promoting weight reduction, because this could further reduce the risks of cardiovascular disease and premature death.
Additional Information
Please access these Web sites via the online version of this summary at
National Diabetes Information Clearinghouse, a service of the US National Institute of Diabetes and Digestive and Kidney Diseases, has information on heart disease and diabetes, on general complications of diabetes, and on the HbA1c test (on this site and some others called A1C test) that measures control of blood sugar over the past 3 months provides general information on type 1 diabetes, its complications, and what people with the disease can do to reduce their risks
The Canadian Diabetes Association offers a cardiovascular risk self-assessment tool and other relevant information
The American Diabetes Association has information on the benefits and challenges of tight blood sugar control and how it is tested
The Juvenile Diabetes Research Foundation funds research to prevent, cure, and treat type 1 diabetes
Diabetes UK provides extensive information on diabetes for patients, carers, and clinicians
PMCID: PMC3462745  PMID: 23055834
7.  Achieved Levels of HbA1c and Likelihood of Hospital Admission in People With Type 1 Diabetes in the Scottish Population 
Diabetes Care  2011;34(9):1992-1997.
People with type 1 diabetes have increased risk of hospital admission compared with those without diabetes. We hypothesized that HbA1c would be an important indicator of risk of hospital admission.
The Scottish Care Information–Diabetes Collaboration, a dynamic national register of diagnosed cases of diabetes in Scotland, was linked to national data on admissions. We identified 24,750 people with type 1 diabetes during January 2005 to December 2007. We assessed the relationship between deciles of mean HbA1c and hospital admissions in people with type 1 diabetes adjusting for patient characteristics.
There were 3,229 hospital admissions. Of the admissions, 8.1% of people had mean HbA1c <7.0% (53 mmol/mol) and 16.3% had HbA1c <7.5% (58 mmol/mol). The lowest odds of admission were associated with HbA1c 7.7–8.7% (61–72 mmol/mol). When compared with this decile, a J-shaped relationship existed between HbA1c and admission. The highest HbA1c decile (10.8–18.4%/95–178 mmol/mol) showed significantly higher odds ratio (95% CI) for any admission (2.80, 2.51–3.12); the lowest HbA1c decile (4.4–7.1%/25–54 mmol/mol) showed an increase in odds of admission of 1.29 (1.10–1.51). The highest HbA1c decile experienced significantly higher odds of diabetes-related (3.31, 2.94–3.72) and diabetes ketoacidosis admissions (10.18, 7.96–13.01).
People with type 1 diabetes with highest and lowest mean HbA1c values were associated with increased odds of admission. People with high HbA1c (>10.8%/95 mmol/mol) were at particularly high risk. There is the need to develop effective interventions to reduce this risk.
PMCID: PMC3161268  PMID: 21788623
8.  Using Web Technology to Support Population-Based Diabetes Care 
Managed clinical networks have been used to coordinate chronic disease management across geographical regions in the United Kingdom. Our objective was to review how clinical networks and multidisciplinary team-working can be supported by Web-based information technology while clinical requirements continually change.
A Web-based population information system was developed and implemented in November 2000. The system incorporates local guidelines and shared clinical information based upon a national dataset for multispecialty use. Automated data linkages were developed to link to the master index database, biochemistry, eye screening, and general practice systems and hospital diabetes clinics. Web-based data collection forms were developed where computer systems did not exist. The experience over the first 10 years (to October 2010) was reviewed.
The number of people with diabetes in Tayside increased from 9694 (2.5% prevalence) in 2001 to 18,355 (4.6%) in 2010. The user base remained stable (~400 users), showing a high level of clinical utility was maintained. Automated processes support a single point of data entry with 10,350 clinical messages containing 40,463 data items sent to external systems during year 10. The system supported quality improvement of diabetes care; for example, foot risk recording increased from 36% in 2007 to 73.3% in 2010.
Shared-care datasets can improve communication between health care service providers. Web-based technology can support clinical networks in providing comprehensive, seamless care across a geographical region for people with diabetes. While health care requirements evolve, technology can adapt, remain usable, and contribute significantly to quality improvement and working practice.
PMCID: PMC3192619  PMID: 21722568
electronic records; information technology; integrated care; managed clinic networks; shared care
9.  Candidate Gene Association Study for Diabetic Retinopathy in Persons with Type 2 Diabetes: The Candidate Gene Association Resource (CARe) 
Cardiovascular disease candidate genes, including genes previously associated with type 2 diabetes and diabetic nephropathy, were not associated with diabetic retinopathy, although a limited number of variants merit further investigation in larger cohorts.
To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).
Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades ≥14 and ≥30. The χ2 analyses for each CARe cohort were combined by Cochran-Mantel-Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods.
Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging α-l-iduronidase (IDUA) (P = 2.1 × 10−5, after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively.
Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts.
PMCID: PMC3183981  PMID: 21873659
10.  Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study 
Diabetes  2009;58(6):1434-1439.
Metformin is actively transported into the liver by the organic cation transporter (OCT)1 (encoded by SLC22A1). In 12 normoglycemic individuals, reduced-function variants in SLC22A1 were shown to decrease the ability of metformin to reduce glucose excursion in response to oral glucose. We assessed the effect of two common loss-of-function polymorphisms in SLC22A1 on metformin response in a large cohort of patients with type 2 diabetes.
The Diabetes Audit and Research in Tayside Scotland (DARTS) database includes prescribing and biochemistry information and clinical phenotypes of all patients with diabetes within Tayside, Scotland, from 1992 onwards. R61C and 420del variants of SLC22A1 were genotyped in 3,450 patients with type 2 diabetes who were incident users of metformin. We assessed metformin response by modeling the maximum A1C reduction in 18 months after starting metformin and investigated whether a treatment target of A1C <7% was achieved. Sustained metformin effect on A1C between 6 and 42 months was also assessed, as was the time to metformin monotherapy failure. Covariates were SLC22A1 genotype, BMI, average drug dose, adherence, and creatinine clearance.
A total of 1,531 patients were identified with a definable metformin response. R61C and 420del variants did not affect the initial A1C reduction (P = 0.47 and P = 0.92, respectively), the chance of achieving a treatment target (P = 0.83 and P = 0.36), the average A1C on monotherapy up to 42 months (P = 0.44 and P = 0.75), or the hazard of monotherapy failure (P = 0.85 and P = 0.56).
The SLC22A1 loss-of-function variants, R61C and 420del, do not attenuate the A1C reduction achieved by metformin in patients with type 2 diabetes.
PMCID: PMC2682689  PMID: 19336679
11.  Blunting of AICAR-induced human skeletal muscle glucose uptake in type 2 diabetes is dependent on age rather than diabetic status 
We demonstrated previously that, in healthy young men, 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) stimulates human muscle 2-deoxyglucose (2DG) uptake without detectable activation of muscle AMP-activated protein kinase (AMPK) but with extracellular-regulated kinase 1/2 (ERK1/2) activation. We tested whether AICAR stimulates muscle 2DG uptake in healthy older patients with or without type 2 diabetes (T2D). Six healthy young subjects (23 ± 3 yr, BMI 25 ± 2 kg/m−2; means ± SE), eight older subjects (59 ± 4 yr, BMI 28 ± 2 kg/m−2), and eight subjects with T2D (62 ± 4 yr, BMI 27 ± 2 kg/m−2) received a 6-h 2DG infusion (prime 10 mg/kg, 6 mg·kg−1·h−1) and AICAR (10 or 20 mg·kg−1·h−1) from 3 to 6 h. Quadriceps biopsies were taken at 0, 3, and 6 h. We determined 1) 2DG uptake, 2) total AMPKα activity, AMPK, acetyl-CoA carboxylase (ACC), and AS160 phosphorylation, and 3) ERK1/2 phosphorylation. Ten milligrams per kilogram per hour AICAR increased 2DG uptake by 2.9 ± 0.7-fold in young men (P < 0.001), 1.8 ± 0.2-fold in older men (P < 0.01), and 1.6 ± 0.1-fold in men with T2D; 20 mg·kg−1·h−1 AICAR increases were 2.5 ± 0.1-fold (older men, P < 0.001) and 2.2 ± 0.2-fold (men with T2D, P < 0.001). At 3-h AMPK activity and AMPK, ACC and AS160 phosphorylation were unchanged, but ERK1/2 phosphorylation increased at both AICAR doses. The fold changes of ERK1/2 phosphorylation and 2DG uptake closely correlated (R2 = 0.55, P = 0.003). AICAR stimulates muscle 2DG uptake in T2D to the same extent as in healthy age-matched controls, but there is an age-related reduction.
PMCID: PMC2681307  PMID: 19190259
5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside; adenosine 5′-monophosphate-activated protein kinase; extracellular-signal-regulated kinase 1/2
12.  Screening Uptake in a Well-Established Diabetic Retinopathy Screening Program 
Diabetes Care  2008;31(11):2131-2135.
OBJECTIVE—To identify criteria that affect uptake of diabetes retinal screening in a community screening program using mobile retinal digital photography units.
RESEARCH DESIGN AND METHODS—Data from the regional diabetes population-based retinal screening program and regional ophthalmology laser database were linked to patient postal code (zip code) data. We used distance from retinal screening event, social deprivation scores, and demographic information to identify risk factors for nonattendance at a diabetes retinal screening event. Patients were subdivided into urban (>125,000 population), other urban (3,000–125,000 population), or rural (<3,000 population) depending on where they lived. Data were collected from 2004 to 2006 inclusive and included 15,150 patients and 32,621 eye screening records.
RESULTS—The mean ± SD age of patients was 63 ± 15 years, and 54% were male. Mean travel time to retinal screening event varied from 7.1 to 17.0 min. For 12% of missed appointments, patients were more likely to be younger, to have longer diabetes duration, to have poor A1C and blood pressure control, to be smokers, and to live in deprived areas. Poor attendance was not associated with sex or distance to retinal screening event.
CONCLUSIONS—Social deprivation is strongly associated with poor attendance at retinal screening events. Time traveled to screening event was not associated with attendance in this study of a mobile retinal screening service, which visited general practitioner surgeries. This data can help inform population-based diabetes retinal screening programs about improving patient uptake.
PMCID: PMC2571062  PMID: 18728235
13.  Poor glycated haemoglobin control and adverse pregnancy outcomes in type 1 and type 2 diabetes mellitus: Systematic review of observational studies 
Glycaemic control in women with diabetes is critical to satisfactory pregnancy outcome. A systematic review of two randomised trials concluded that there was no clear evidence of benefit from very tight versus tight glycaemic control for pregnant women with diabetes.
A systematic review of observational studies addressing miscarriage, congenital malformations and perinatal mortality among pregnant women with type 1 and type 2 diabetes was carried out. Literature searches were performed in MEDLINE, EMBASE, CINAHL and Cochrane Library. Observational studies with data on glycated haemoglobin (HbA1c) levels categorised into poor and optimal control (as defined by the study investigators) were selected. Relative risks and odds ratios were calculated for HbA1c and pregnancy outcomes. Adjusted relative risk estimates per 1-percent decrease in HbA1c were calculated for studies which contained information on mean and standard deviations of HbA1c.
The review identified thirteen studies which compared poor versus optimal glycaemic control in relation to maternal, fetal and neonatal outcomes. Twelve of these studies reported the outcome of congenital malformations and showed an increased risk with poor glycaemic control, pooled odds ratio 3.44 (95%CI, 2.30 to 5.15). For four of the twelve studies, it was also possible to calculate a relative risk reduction of congenital malformation for each 1-percent decrease in HbA1c, these varied from 0.39 to 0.59. The risk of miscarriage was reported in four studies and was associated with poor glycaemic control, pooled odds ratio 3.23 (95%CI, 1.64 to 6.36). Increased perinatal mortality was also associated with poor glycaemic control, pooled odds ratio 3.03 (95%CI, 1.87 to 4.92) from four studies.
This analysis quantifies the increase in adverse pregnancy outcomes in women with diabetes who have poor glycaemic control. Relating percentage risk reduction in HbA1c to relative risk of adverse pregnancy events may be useful in motivating women to achieve optimal control prior to conception.
PMCID: PMC1635059  PMID: 17074087
14.  Association of common variation in the PPARA gene with incident myocardial infarction in individuals with type 2 diabetes: A Go-DARTS study 
Nuclear Receptor  2005;3:4.
Common variants of the PPARA gene have been found to associate with ischaemic heart disease in non diabetic men. The L162V variant was found to be protective while the C2528G variant increased risk. L162V has also been associated with altered lipid measures. We therefore sought to determine the effect of PPARA gene variation on susceptibility to myocardial infarction in patients with type 2 diabetes. 1810 subjects with type 2 diabetes from the prospective Go-DARTS study were genotyped for the L162V and C2528G variants in the PPARA gene and the association of the variants with incident non-fatal myocardial infarction was examined. Cox's proportional hazards was used to interrogate time to event from recruitment, and linear regression for analysing association of genotype with quantitative clinical traits.
The V162 allele was associated with decreased risk of non-fatal myocardial infarction (HR = 0.31, 95%CI 0.10–0.93 p = 0.037) whereas the C2528 allele was associated with increased risk (HR = 2.77 95%CI 1.34–5.75 p = 0.006). Similarly V162 was associated with a later mean age of diagnosis with type 2 diabetes and C2582 an earlier age of diagnosis. C2528 was also associated with increased total cholesterol and LDL cholesterol, which did not account for the observed increased risk. Haplotype analysis demonstrated that when both rare variants occurred on the same haplotype the effect of each was abrogated.
Genetic variation at the PPARA locus is important in determining cardiovascular risk in both male and female patients with diabetes. This genotype associated risk appears to be independent of the effect of these genotypes on lipid profiles and age of diagnosis with diabetes.
PMCID: PMC1318486  PMID: 16309557
15.  Male preponderance in early diagnosed type 2 diabetes is associated with the ARE insertion/deletion polymorphism in the PPP1R3A locus 
BMC Genetics  2003;4:11.
The ARE insertion/deletion polymorphism of PPP1R3A has been associated with variation in glycaemic parameters and prevalence of diabetes. We have investigated its role in age of diagnosis, body weight and glycaemic control in 1,950 individuals with type 2 diabetes in Tayside, Scotland, and compared the ARE2 allele frequencies with 1,014 local schoolchildren.
Men homozygous for the rarer allele (ARE2) were younger at diagnosis than ARE1 homozygotes (p = 0.008). Conversely, women ARE2 homozygotes were diagnosed later than ARE1 homozygotes (p = 0.036). Thus, men possessing the rarer (ARE2) allele were diagnosed with type 2 diabetes earlier than women (p < 0.000001). In contrast, there was no difference in age of diagnosis by gender in those individuals carrying only the common ARE1 variant. Furthermore, although there was no difference in the frequency between the children and the type 2 diabetic population overall, marked differences in allele frequencies were noted by gender and age-of diagnosis. The ARE2 allele frequency in early diagnosed males (diagnosed earlier than the first quartile of the overall ages at diagnosis) was higher than that found in both later diagnosed males and healthy children (p = 0.021 and p = 0.03 respectively). By contrast, the frequency in early diagnosed females was significantly lower than later diagnosed females and that found in children (p = 0.021 and p = 0.037).
Comparison of the male to female ratios at different ages-diagnosed confirms a known phenomenon that men are much more prone to early type 2 diabetes than women. When this feature was examined by the common ARE 1/1 genotype we found that the male to female ratio remained at unity with all ages of diagnosis, however, carriers of the ARE2 variant displayed a marked preponderance of early male diagnosis (p = 0.003).
The ARE2 allele of PPP1R3A is associated with a male preponderance to early diagnosed type 2 diabetes. Susceptibility to type 2 diabetes in later life is not modulated by the ARE2 allele in either sex.
PMCID: PMC169162  PMID: 12831406
16.  Contemporary Risk of Hip Fracture in Type 1 and Type 2 Diabetes: A National Registry Study From Scotland† 
Journal of Bone and Mineral Research  2013;29(5):1054-1060.
The purpose of this study was to compare contemporary risk of hip fracture in type 1 and type 2 diabetes with the nondiabetic population. Using a national diabetes database, we identified those with type 1 and type 2 diabetes who were aged 20 to 84 years and alive anytime from January 1, 2005 to December 31, 2007. All hospitalized events for hip fracture in 2005 to 2007 for diabetes patients were linked and compared with general population counts. Age- and calendar-year-adjusted incidence rate ratios were calculated by diabetes type and sex. One hundred five hip fractures occurred in 21,033 people (59,585 person-years) with type 1 diabetes; 1421 in 180,841 people (462,120 person-years) with type 2 diabetes; and 11,733 hip fractures over 10,980,599 person-years in the nondiabetic population (3.66 million people). Those with type 1 diabetes had substantially elevated risks of hip fracture compared with the general population incidence risk ratio (IRR) of 3.28 (95% confidence interval [CI] 2.52–4.26) in men and 3.54 (CI 2.75–4.57) in women. The IRR was greater at younger ages, but absolute risk difference was greatest at older ages. In type 2 diabetes, there was no elevation in risk among men (IRR 0.97 [CI 0.92–1.02]) and the increase in risk in women was small (IRR 1.05 [CI 1.01–1.10]). There remains a substantial elevation relative risk of hip fracture in people with type 1 diabetes, but the relative risk is much lower than in earlier studies. In contrast, there is currently little elevation in overall hip fracture risk with type 2 diabetes, but this may mask elevations in risk in particular subgroups of type 2 diabetes patients with different body mass indexes, diabetes duration, or drug exposure. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
PMCID: PMC4255308  PMID: 24155126

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